Method of inhibiting bacterial growth with certain selected 3-chloro-2-oxazolidinones

ABSTRACT

Antibacterially effective 3-chloro-2-oxazolidinones are prepared by chlorination of an appropriate 2-oxazolidinone either with elemental chlorine in an aqueous medium or with a mono-, di- or trichloroisocyanuric acid (cyanuric chloride) in an inert organic solvent. The 2-oxazolidinones are, in turn, prepared by reaction of an appropriate ethanolamine either with a di-lower-alkyl carbonate in the presence of a strong base or with urea at an elevated temperature.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of our earlier copendingapplication, Ser. No. 533,945, filed Dec. 18, 1974, now U.S. Pat. No.3,931,213.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to 3-chloro-2-oxazolidinones useful in the art ofchemistry and having antibacterial activity.

2. Description of the Prior Art

Walles U.S. Pat. No. 3,591,601 (patented July 6, 1971) discloses certain3-halo-2-oxazolidinones having the formula: ##STR1## where X is broadlydefined as bromine or chlorine, and R₁, R₂, R₃ and R₄ are broadlydefined, inter alia, as hydrogen or lower-alkyl containing from one tofour carbon atoms. The compounds are said to be useful "in germicidal,bleaching, and chemical reaction applications."

While the above definitions are broadly embracive of compounds having aquaternary carbon at the 4- and/or 5- positions of the oxazolidinonering, i.e. compounds where either each of R₁, R₂, R₃ and R₄ islower-alkyl or compounds where each of R₁ and R₂ or each of R₃ and R₄ islower-alkyl (the other pair being hydrogen), such compounds are notspecifically taught by Walles, who discloses only compounds where the 4-and 5-carbon atoms are either unsubstituted or where either one or bothof the 4- and 5-carbon atoms bear a single lower-alkyl group. Thus, ofthe 2-oxazolidinones having the above general structure where each ofR₁, R₂, R₃ and R₄ are either hydrogen or lower-alkyl, Walles disclosesonly the following species. (The "Walles Cpd. Nos." are adopted here forreference purposes hereinafter.)

    ______________________________________                                        Walles Cpd. No.                                                                           R.sub.1  R.sub.2 R.sub.3                                                                              R.sub.4                                                                             X                                   ______________________________________                                        1           CH.sub.3 H       H      H     Cl                                  2           C.sub.2 H.sub.5                                                                        H       H      H     Cl                                  3           H        H       H      H     Cl                                  4           CH.sub.3 H       H      H     Br                                  5           CH.sub.3 H       CH.sub.3                                                                             H     Cl                                  6           C.sub.4 H.sub.9                                                                        H       H      H     Br                                  ______________________________________                                    

Certain of the above-listed Walles compounds have been prepared and ithas been found that they are somewhat unstable and consequently havelimited usefulness as germicidal agents. On the other hand, it has beensurprisingly found that certain compounds within the ambit of the verybroad disclosure of the patentee, but not specifically contemplatedthereby, are surprisingly stable, in contrast with the compoundsactually prepared by Walles, and possess unexpected advantageousproperties as germicides.

SUMMARY OF THE INVENTION

Thus, in a composition of matter aspect, the present invention relatesto certain 3-chloro-4,4-di-lower-alkyl-2-oxazolidinones and3-chloro-5,5-di-lower-alkyl-2-oxazolidinones useful as germicidalagents.

The invention also relates to a method of inhibiting the growth ofbacteria comprising treating bacteria with a bactericidally effectiveamount of the said 3-chloro-4,4-di-lower-alkyl-2-oxazolidinones or3-chloro-5,5-di-lower-alkyl-2-oxazolidinones and to germicidalcompositions containing a bactericidally effective amount of the said3-chloro-4,4-di-lower-alkyl-2-oxazolidinones and3-chloro-5,5-di-lower-alkyl-2-oxazolidinones as the active ingredient inan aqueous medium.

In a process aspect, the invention relates to a process for preparingthe 3-chloro-4,4-di-lower-alkyl-2-oxazolidinones and3-chloro-5,5-di-lower-alkyl-2-oxazolidinones comprising reacting a4,4-di-lower-alkyl-2-oxazolidinone or a5,5-di-lower-alkyl-2-oxazolidinone with chlorine in an aqueous medium.

DETAILED DESCRIPTION INCLUSIVE OF THE PREFERRED EMBODIMENTS

More specifically, this invention relates to 3-chloro-2-oxazolidinoneshaving the formula: ##STR2## where either R₁ and R₂ are the same ordifferent lower-alkyl group, and R₃ and R₄ are each hydrogen or R₁ andR₂ are each hydrogen, and R₃ and R₄ are the same or differentlower-alkyl group. Preferred compounds within the ambit of the inventionas described above are the compounds where R₁ and R₂ are each hydrogen,and R₃ and R₄ are the same or different lower-alkyl groups, andparticularly preferred compounds are those of the latter group where R₅and R₄ are the same lower-alkyl. It will be appreciated from theforegoing that an essential feature of the compounds of the presentinvention is the presence of a quaternary carbon atom at either the 4-or 5-position of the 2-oxazolidinone ring.

As used herein, the term lower-alkyl means saturated, aliphatichydrocarbon groups, either straight or branched-chain, containing fromone to four carbon atoms, as exemplified by methyl, ethyl, propyl,isopropyl, butyl or isobutyl.

The compounds of formula I are prepared by chlorination with chlorine ofthe corresponding unhalogenated 4,4-di-lower-alkyl-2-oxazolidinone or5,5-di-lower-alkyl-2-oxazolidinone having the formula: ##STR3## whereR₁, R₂, R₃ and R₄ have the meanings given above. The reaction is carriedout in an aqueous medium and preferably at a temperature in the rangefrom 0° C. to 10° C. Although higher reaction temperatures can be used,no particular advantage is gained thereby, because the halogenated finalproducts can be hydrolyzed by the solvent, and the rate of hydrolysisincreases with increase in temperature.

Alternatively, the compounds of formula I are prepared by atranshalogenation process involving reaction of a 2-oxazolidinone offormula II with a mono-, di- or trihalogenated isocyanuric acid, forexample trichloroisocyanuric acid (cyanuric chloride) in an inertorganic solvent, for example chloroform, methylene chloride or ethylenechloride. Reaction usually takes place at ambient temperature.

The unhalogenated 2-oxazolidinones of formula II are, in turn, preparedby reaction of an alkanolamine of formula III with a di-lower-alkylcarbonate in the presence of a strong base, for example an alkali metallower-alkoxide, as represented by the reaction: ##STR4## where R₁, R₂,R₃ and R₄ have the meanings given above. The reaction is carried out byheating the reactants above the boiling point of the lower-alkanolproduced in the reaction, which is distilled off as it forms.

Alternatively, the compounds of formula II are prepared by reacting analkanolamine of formula III with urea at an elevated temperature, i.e. atemperature in the range from 150°-250° C., as represented by thereaction: ##STR5## where R₁, R₂, R₃ and R₄ have the meanings givenabove.

The alkanolamines of formula III are a generally known class ofcompounds.

The compounds of formula I have been tested in a standard biologicaltest procedure, the germidical efficiency test to be describedhereinbelow, and found to possess bactericidal activity when testedagainst Staphylococcus aureus ATCC 6538. The compounds are thus usefulas bactericidal agents.

The compounds of the invention can be prepared for use by dissolvingthem in an aqueous medium, preferably buffered to pH 7.0, and applied tosurfaces or areas to be disinfected by spraying, swabbing or immersion.

The molecular structures of the compounds of the invention were assignedon the basis of their method of preparation, and study of their infraredand proton magnetic resonance spectra and were confirmed by thecorrespondence between calculated and found values for elementaryanalyses for the elements.

In the following specific examples, which illustrate the preparation ofthe compounds of the invention as well as reference compounds preparedfor purposes of comparison, all melting points are uncorrected.

PREPARATION OF THE UNHALOGENATED 2-OXAZOLIDINONES OF FORMULA IIPreparation 1

A. A mixture of 61.0 g. (1.0 mole) of ethanolamine and 190 ml. (1.7moles) of diethyl carbonate was heated to distill approximately 35 ml.of diethyl carbonate in order to ensure dryness. The mixture was cooledto 50° C., and 5 ml. of 25% sodium methoxide in methanol solution wasadded. The mixture was heated to remove approximately 100 ml. ofethanol. On cooling, the residue was recrystallized from chloroform togive 44.8 g. (0.51 mole, 51%) of 2-oxazolidinone, m.p. 86°-88° C.; pmr(CDCl.sub. 3) δ2.8-4.2 (AA'BB', 4H) and 6.0 (bs, 1H) ppm. (Lit. m.p.87°-89° C., Homeyer, U.S. Pat. No. 2,399,118).

Following a procedure similar to that described in Preparation 1, part Aabove, the following compounds of formula II were similarly prepared:

B. 4-Methyl-2-oxazolidinone, b.p. 140°-146°/5 mm; ir-3280, 2980, 1750,1400, 1240, 1020, and 920 cm⁻ ¹ ; pmr (CDCl.sub. 3) δ6.8 (bs, 1H), 4.4(m, 1H), 3.9 (m, 2H) and 1.3 (d, 3H, J=6Hz) ppm, [Lit. b.p.120°-125°/2.3 mm, Johnston et al; J. Med. Chem., 14, 345 (1971)].

C. 4,5-Dimethyl-2-oxazolidinone, b.p. 95°-100°/0.15 mm; ir-3300, 2990,1750, 1380, 1240, 1060 and 975 cm⁻ ¹, pmr (CDCl.sub. 3) δ6.9 (bs, 1H),5.2-3.2 (m, 2H) and 1.6-1.0 (m, 6H) ppm.

Anal. Calcd. for C₅ H₉ NO₂ : C,52.17; H,7.89; N,12.17. Found: C,52.37;H,8.10; N,12.35.

D. 5-Methyl-2-oxazolidinone, b.p. 123°-125° C./0.6 mm.; ir-3320 (N-H)and 1740 (C=O) cm⁻ ¹ ; pmr (CDCl.sub. 3) δ6.73 (bs, 2H), 4.80 (m, 1H),4.0-3.0 (m, 2H) and 1.43 (d, 3H) ppm.

Anal. Calcd. for C₄ H₇ NO₂ : C,47.51; H,6.98; N,13.86. Found: C,47.70;H,7.11; N,13.73.

E. 5-Ethyl-2-oxazolidinone, m.p. 50.5°-52° C.; ir-3280 (NH) and 1745(C=O) cm⁻ ¹ ; pmr (CDCl.sub. 3) δ6.7 (bs, 1H), 4.60 (m, 1H), 4.0-3.0 (m,2H) and 1.03 (t, 3H) ppm.

Anal. Calcd. for C₅ H₉ NO₂ : C,52.16; H,7.88; N,12.17. Found: C,52.29;H,7.87; N,12.25.

F. 4,4-Dimethyl-2-oxazolidinone, m.p. 49°-51°; pmr (CDCl.sub. 3) δ7.0(bs, 1H), 4.03 (s, 2H), and 1.30 (s, 6H) ppm, [Lit, m.p. 55°-56°,Homeyer, U.S. Pat. No. 2,399,118].

G. 4-Ethyl-4-Methyl-2-oxazolidinone, b.p. 110°-113°/0.3 mm; ir-3300,3000, 1760, and 1040 cm⁻ ¹ ; pmr (CDCl.sub. 3) δ7.4 (bs, 1H), 4.1 (q,2H), 1.6 (bq, 2H), 1.3 (s, 3H) and 1.0 (t, 3H) ppm.

Anal. Calcd. for C₆ H₁₁ NO₂ : C,55.79; H,8.59; N,10.85. Found: C,55.23;H,8.58; N,10.68.

PREPARATION 2

A mixture of 22.25 g. (0.25 mole) of 2-aminomethyl-2-propanol and 30.0g. (0.5 mole) of urea were heated together at 170°-180° C. for 20minutes, and the temperature was then increased to 200°-210° C. for anadditional 20 minutes. On cooling, the brown solid was dissolved inwater, the aqueous layer extracted with dichloromethane and the extractscombined and dried over anhydrous sodium sulfate. Following filtration,the dichloromethane was removed under reduced pressure to afford 13.1 g.(0.11 mole, 44%) of 5,5-dimethyl-2-oxazolidinone, m.p. 74°-77° C.;ir-3290 (N-H) and 1755 (C=0) cm⁻ ¹ ; pmr (CDCl.sub. 3) δ1.50 (s, 6H),3.37 (s, 2H) and 6.77 bs, 1H) ppm. [Lit. m.p. 79°-82° C., Close, J. Am.Chem. Soc. 73, 95 (1951)].

PREPARATION OF THE 3-CHLORO-2 -OXAZOLIDINONES OF FORMULA I Example 1

A. Chlorine was bubbled through a solution of 8.7 g. (0.10 mole) of2-oxazolidinone in 30 ml. of water at 0° C. for 30 minutes. A whitesolid precipitated, and the mixture was extracted with dichloromethane.The extracts were combined and dried over anhydrous sodium sulfate.Following filtration, the dichloromethane was removed under reducedpressure to afford a white solid, m.p. 58.5°-60° C. Sublimation of thismaterial at 40° C./0.2 mm. gave 8.57 g. (0.071 mole, 71%) of3-chloro-2-oxazolidinone (Walles Cpd. 3), m.p. 59°-61° C.; uv (H₂ O)λmax 248 nm, ε = 296 M⁻ ¹ cm⁻ ¹ ; pmr (CDCl.sub. 3) δ3.6-5.0 (AA'BB', 4H)ppm.

Anal. Calcd. for C₃ H₄ ClNO.sub. 2 : C,29.65; H,3.32; N,11.53; Cl,29.2Found: C,29.95; H,3.65; N,11.77; Cl,28.7.

Following a procedure similar to that described in Example 1, part Aabove, the following compounds of formula I were similarly prepared:

B. 3-Chloro-4-methyl-2-oxazolidinone, b.p. 85°-90° C./1 mm.; ir-3000,1780, 1390, 1195 and 1040 cm⁻ ¹ ; pmr (CDCl.sub. 3) δ4.5 (m, 1H), 4.0(m, 2H) and 1.4 (d, 3H, J=6Hz) ppm.

Anal. Calcd. for C₄ H6ClNO.sub. 2 : C,35.44; H,4.46; N,10.33; Cl,26.2.Found: C,35.64; H,4.59; N,10.14; Cl,26.5.

C. 3-Chloro-4,5-dimethyl-2-oxazolidinone (Walles Cpd. 5), b.p. 60°-65°C./0.2 mm.; ir-3000, 1795, 1470, 1400, 1380, 1320 and 1215 cm⁻ ¹ ; pmr(CDCl.sub. 3) δ3.2-5.1 (m, 2H) and 1.4 (q with fine structure, 6H) ppm.

Anal. Calcd. for C₅ H₈ ClNO₁ 2: C,40.15; H,5.39; N,9.37; Cl,23.7 Found:C,40,37; H,5.35; N,8.75; Cl,21.8.

D. 3-Chloro-5-methyl-2-oxazolidinone (Walles Cpd. 1), b.p. 70-73° C./0.2mm.; ir-1765 cm⁻ ¹ ; pmr (CDCl.sub. 3) δ4.80 (m, 1H), 4.2-3.2 (m, 2H)and 1.50 (d, 3H) ppm.

Anal. Calcd. for C₄ H₆ ClNO.sub. 2 : C,35.44; H,4.46; N,10.33; Cl,26.2.Found: C,35.90; H,5.03; N,9.71; Cl,25.0.

E. 3-Chloro-5-ethyl-2-oxazolidinone (Walles Cpd. 2), b.p. 88°-90° C./0.3mm.; ir-1780 cm⁻ ¹ ; pmr (CDCl.sub. 3) δ4.60 (m, 1H), 4.2-3.2 (m, 2H),1.77 (m, 2H) and 1.05 (t, 3H) ppm.

Anal. Calcd. for C₅ H₈ ClNO.sub. 2 : C,40.15; H,5.39; N,9.37; Cl,23.7.Found: C,40.36; H,5.45; N,9.25; Cl,23.8.

F. 3-Chloro-4,4-dimethyl-2-oxazolidinone, m.p. 71°-72.5° C., sublimes at60° C./0.25 mm.; uv (H₂ O) λ max 248 nm, ε = 274 M⁻ ¹ cm⁻ ¹ ; pmr(CDCl.sub. 3) δ4.23 (s, 2H) and 1.40 (s, 6H) ppm.

Anal. Calcd. for C₅ H₈ ClNO.sub. 2 : C,40.15; H,5.39; N,9.37; Cl,23.7.Found: C,40.36; H,5.36; N,9.35; Cl,23.4.

G. 3-Chloro-5,5-dimethyl-2-oxazolidinone, m.p. 58°-60° C., sublimes at50° C./0.5 mm.; ir (NaCl) 3000, 2900, 1770, 1290 and 1125 cm⁻ ^(;) pmr(CDCl.sub. 3) δ3.6 (s, 2H) and 1.6 (s, 6H) ppm.

Anal. Calcd. for C₅ H₈ ClNO.sub. 2 : C,40.15; H,5.39; N,9.37; Cl,23.7.Found: C,40.39; H,5.36; N,9.42; Cl,22.6.

H. 3-Chloro-4-ethyl-4-methyl-2-oxazolidinone, ir-3000, 1780 and 1075 cm⁻¹ ; pmr (CDCl.sub. 3) δ4.3 (t, 2H), 1.8 (bq, 2H), 1.4 (s, 3H) and 0.98(t, 3H) ppm.

Anal. Calcd. for C₆ H₁₀ ClNO.sub. 2 : C,44.04; H,6.12; N,8.57; Cl,21.7.Found: C,44.23; H,6.30; N,8.29 Cl,21.2.

EXAMPLE 2

To a suspension of 4.0 g. (0.35 mole) of trichloroisocyanuric acid in 20ml. of dichloromethane was added 4.0 g. (0.035 mole) of4,5-dimethyl-2-oxazolidinone. The mixture was stirred for two hours, awhite solid which separated was removed by filtration, and the filtratetaken to dryness under reduced pressure. Distillation of the residuegave 3.4 g. (0.023 mole, 66%) of 3-chloro-4,5-dimethyl-2-oxazolidinone,b.p. 85°-90° C./0.5 mm., identical with that obtained by the proceduredescribed in Example 1, part C above as shown by infrared and protonmagnetic resonance spectra of the two samples.

The compounds of the invention and certain reference compounds weretested in the germidical efficiency test, a modification of the standardserial dilution test, against Staphylococcus aureus ATCC 6538. In thegermicidal efficiency test, instead of determining the minimuminhibitory concentration as in the serial dilution test procedure, thetime required to effect complete sterilization of the micro-organismwhen exposed to a given concentration of the test substance isdetermined. This procedure affords a basis of comparison of the timedependent efficacies of the various test substances which gives ameasure not only of the germidical efficacy of the test species but,since as will be seen germicidal efficiency of the N-chloro compoundsgenerally tends to diminish with time, apparently owing to decompositionof, and therefore dilution of, the active species, the test procedurealso provides an indication of the efficacy to be expected at varyingtime intervals after solution of the test species in the applicationmedium. The test procedure is described as follows: A stock solution ofknown concentration of each compound to be tested was prepared in 0.1Msodium dihydrogen phosphate buffered to pH 7.0. To 5 ml. of the testsolution was added 0.2 ml. of an overnight broth culture containing from6×10⁶ to 8×10⁶ organisms/ml. of Staphylococcus aureus ATCC 6538 and 5 g.of gelysate peptone and 3 g. of beef extract per 1000 ml. of water. Attime intervals of 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 and 30 minutes,a loop of this suspension was subcultured into 5 ml. of sterile nutrientbroth (5 g. of gelysate peptone and 3 g. of beef extract/1000 ml. ofwater), and the samples were incubated at 37° C. for 7 days with dailyobservation for evidence of bacterial growth. The time interval in whichno bacterial growth was observed after the incubation period in aparticular sample was recorded as the end point.

The germicidal kill times so-obtained at various concentrations of thecompounds of the invention and of certain reference compounds are givenin Table A below. The compounds are identified in each case by theExample number above where the compounds are described. Here andelsewhere in the specification that follows, concentrations areexpressed in parts per million (ppm) of "positive" chlorine, which wasdetermined in each instance by addition of excess aqueous potassiumiodide to an acidified solution of the test compound and titration ofthe iodine liberated with standard sodium thiosulfate solution.

                  Table A                                                         ______________________________________                                        Compound/      Concentration Bactericidal                                     Example No.    ppm .sup.+Cl  Time (Minutes)                                   ______________________________________                                         ##STR6##      465 281  157 70                                                                             1 2 7  10<t ≦15                           1A (Walles Cpd. 3)                                                             ##STR7##      610 303 131   1  4 7                                           IB                                                                             ##STR8##      490 295 173 117                                                                             4  5 10<t≦15 10                           1C (Walles Cpd. 5)                                                             ##STR9##      548 383 190 74                                                                              0.5 2 15<t≦30  >30                        1D (Walles Cpd. 1)                                                             ##STR10##     535 372 161 96                                                                              1  3 2 6                                         1E (Walles Cpd. 2)                                                             ##STR11##     508 368 195 148                                                                             2 3 5 5                                          1F                                                                             ##STR12##     473 104       7 15<t≦30                                 1G                                                                            ______________________________________                                    

The stabilities and the time-dependent efficacies of the claimed andreference species were determined by comparing the contact germicidaltimes and the initial and final concentrations of positive chlorine insolutions of the test species in 0.1M sodium dihydrogen phosphatebuffered to pH 7.0 before and after 14 day incubation of the solutionsat 40° C. The results are given in Table B below, where the columnsheaded "B_(c) Time" refers to the bactericidal time in minutes.

                                      Table B                                     __________________________________________________________________________               Initial Concn. Final Concn.                                        Example No.                                                                              ppm .sup.+Cl                                                                           B.sub.c Time                                                                        ppm .sup.+Cl                                                                          B.sub.c Time                                __________________________________________________________________________    1A (Walles Cpd. 3)                                                                       465      1     30      >30                                         1B         610      1     14      >30                                         1C (Walles Cpd. 5)                                                                       490      4     51      15<t≦30                              1D (Walles Cpd. 1)                                                                       548      0.5   34      >30                                         1E (Walles Cpd. 2)                                                                       535      1     15      >30                                         1F         534      2      527    2                                           1G         473      7     43      10<t≦15                              1H         555      3      553    3                                           __________________________________________________________________________

These results show that, with the exception of the compound of Example1C (Walles Cpd. 5), each of the reference compounds decomposed over thetest period to the point where each had lost measurable bactericidalactivity. On the other hand, 3-chloro-4,4-dimethyl-2-oxazolidinone and3-chloro-4-ethyl-4-methyl-2-oxazolidinone, the compounds of Examples 1Fand 1H, respectively, had decomposed only slightly over the test periodand had retained the original level of bactericidal activity, while3-chloro-5,5-dimethyl-2-oxazolidinone, the compound of Example 1G,although substantially decomposed over the test period, neverthelessretained a good measure of bactericidal activity superior to each of thereference species, including that of Example 1C.

A further measure of the relative stabilities of the reference andclaimed species was obtained by measuring the hydrolytic stability ofthe various species in 0.1M sodium dihydrogen phosphate buffered to pH7.0 at 40°. For each species, the rate of change in the concentration ofpositive chlorine in the solution was measured by the volume of standardthiosulfate required to titrate a series of aliquots of a standardvolume of the solution at various time intervals using potassiumiodide/sodium thiosulfate as detailed above. The volumes of thiosulfaterequired to titrate each sample so obtained were interpreted asfirst-order kinetic processes. The hydrolytic stabilities of thereference and claimed species under the experimental conditions werecharacterized by the reaction rate constants and half-lives obtainedfrom a linear regression analysis of the experimental data. The resultsobtained are given in Table C below and are also shown in FIG. 1 wherethe volumes in milliliters of standard thiosulfate required to titratethe positive chlorine in the various samples are plotted as ordinateagainst time in days as abscissa.

                                      Table C                                     __________________________________________________________________________                          Rate Constant                                                                          Correlation                                    Example No.                                                                              Half-Life (Hours)                                                                        kx10.sup.-.sup.2 (hr.sup.-.sup.1)                                                      Coefficient                                    __________________________________________________________________________    1A (Walles Cpd. 3)                                                                       45         1.55     0.9995                                         1B         10.9       6.33     0.9825                                         1C (Walles Cpd. 5)                                                                       38.5       1.80     0.9929                                         1F         2038       0.034    0.9899                                         1G         86.6       0.80     0.9763                                         __________________________________________________________________________

These results again demonstrate the unusual stability of3-chloro-4,4-dimethyl-2-oxazolidinone, the compound of Example 1F. Theyalso show that, although the isomeric3-chloro-5,5-dimethyl-2-oxazolidinone of Example 1G is somewhat lessstable than the corresponding 4,4-dimethyl compound, surprisingly thehalf-life of the former is from around twice to eight times as great asthe half-lives of the reference species studied.

As a final measure of the relative stabilities of the claimed and thereference species, the stabilities of the 3-chloro-2-oxazolidinones inthe neat state (i.e. the pure materials containing no added diluent oradulterant) were determined at 40° C. except in those cases where thecompound proved to be so unstable that no significant data could beaccumulated. In those instances, the data were acquired at ambienttemperature (approximately 23° C.). The method used was similar to thatdescribed above in which the rate of disappearance of "positive"chlorine was followed iodometrically by titration of iodine liberatedfrom added potassium iodide with standard sodium thiosulfate solution.Samples of the compounds were individually sealed in ampoules and storedin the dark at 23° C. or 40° C. and weighed amounts removed from time totime for analysis. The results obtained are given in Table D below.

                  Table D                                                         ______________________________________                                        Compound - Example 1A                                                                           Compound - Example 1B                                       (Walles Cpd. 3) (T=40 ° C.)                                                              (T=23° C.)                                           Time (Hrs.)                                                                              % Cl       Time (Hrs.)   % Cl                                      0          28.9       0             26.5                                      2          27.4       3             25.9                                      18.5       25.9       5             25.3                                      24         26.9       6.5           25.0                                      54         27.2       9             25.0                                      72         24.8       10.5          24.1                                      80         23.5       21.5          21.7                                      98         26.2       24.5          21.1                                      144         8.7       29            14.4                                      168         0.4       30            12.4                                                            32             6.1                                                            35             2.0                                                            45            0                                         Compound - Example 1C                                                                           Compound - Example 1F                                       (Walles Cpd. 5) (T=23° C.)                                                               (T=40° C.)                                           Time (Hrs.)                                                                              % Cl       Time (Days)   % Cl                                      0          21.8       0             23.4                                      3          20.8       1             23.0                                      5          8.2        2             23.8                                      7.5        0.47       7             23.5                                      24         0.17       35            24.2                                                            49            23.3                                      Compound - Example 1G                                                                           Compound - Example 1H                                       (T=40° C.) (T=40° C.)                                           Time (Days)                                                                              % Cl       Time (Days)   % Cl                                      0          19.6        0            21.7                                      1          22.1       2             23.6                                      4          23.7       5             21.1                                      7          16.5       10            20.7                                      11         18.1       14            21.0                                      15         14.4       18            20.6                                      19         10.0       25            18.2                                      22         0          39            22.3                                                            53            20.2                                                            164           19.6                                      ______________________________________                                    

For each of the compounds analyzed as indicated above, percent chlorinewas plotted as ordinate against time in days as abscissa onsemi-logarithmic paper and the points connected by a smooth curve foreach compound. Inspection of plots so-made, which are shown in FIG. 2,again shows the surprising stability of3-chloro-4,4-dimethyl-2-oxazolidinone (Example 1F),3-chloro-4-ethyl-4-methyl-2-oxazolidinone (Example 1H) and3-chloro-5,5-dimethyl-2-oxazolidinone (Example 1G) as compared with thevarious reference species.

We claim:
 1. A method of inhibiting bacterial growth which comprisesapplying to said bacterial growth, an antibacterial effective amount ofa compound having the formula: ##STR13## wherein either R₁ and R₂ arethe same or different non-tertiary lower alkyl, and R₃ and R₄ are eachhydrogen or R₁ and R₂ are each hydrogen, and R₃ and R₄ are the same ordifferent non-tertiary lower-alkyl.
 2. The method of claim 1, wherein R₁and R₂ are each hydrogen, and R₃ and R₄ are the same or differentlower-alkyl.
 3. The method of claim 1, wherein R₃ and R₄ are eachhydrogen, and R₁ and R₂ are the same or different lower-alkyl.
 4. Themethod of claim 2, wherein R₃ and R₄ are the same lower-alkyl.
 5. Themethod of claim 4, wherein said compound is3-chloro-4,4-dimethyl-2-oxzolidinone.
 6. The method of claim 2, whereinsaid compound is 3-chloro-4-ethyl-4-methyl-2-oxazolidinone.
 7. Themethod of claim 3, wherein said compound is3-chloro-5,5-dimethyl-2-oxazolidinone.
 8. A composition for inhibitingbacterial growth which comprises an antibacterial effective amount of acompound having the formula: ##STR14## wherein either R₁ and R₂ are thesame or different non-tertiary lower-alkyl, and R₃ and B₄ are eachhydrogen or R₁ and R₂ are each hydrogen, and R₃ and R₄ are the same ordifferent non-tertiary lower-alkyl, as the active ingredient in anaqueous medium.
 9. The composition of claim 8, wherein R₁ and R₂ areeach hydrogen, and R₃ and R₄ are the same or different lower-alkyl. 10.The composition of claim 8, wherein R₃ and R₄ are each hydrogen, and R₁and R₂ are the same or different lower-alkyl.
 11. The composition ofclaim 9, wherein R₃ and R₄ are the same lower-alkyl.
 12. The compositionof claim 11, wherein said compound is3-chloro-4,4-dimethyl-2-oxazolidinone.
 13. The composition of claim 9,wherein said compound is 3-chloro-4-ethyl-4-methyl-2-oxazolidinone. 14.The composition of claim 10, wherein said compound is3-chloro-5,5-dimethyl-2-oxzaolidinone.